1. STOP-HF Investigators St. Vincent’s / St. Michael’s Hospitals and Collaborative GP Group Dublin, Ireland The Saint Vincents Screening To Prevent Heart Failure (STOP-HF) Study A Multicentre, Prospective, Randomised, Controlled Trial of Natriuretic Peptide Based Screening And Collaborative Care To Reduce The Prevalence of Left Ventricular Dysfunction and Heart Failure

2. STOP-HF: Background  Prevention of heart failure is a “Holy Grail” of cardiovascular care  Present approaches are suboptimal  Risk differentiation based on clinical criteria may be limited  Biomarkers may help to focus care to where it is most needed

3. Individualising Risk with NP  Peptide secreted in response to  Pressure / Volume Overload  Ischemia  Fibro-inflammation  Adds to routine risk prediction  NP reflects established CV insult rather than risk of CV damage Framingham Cohort, Wang et al. NEJM 2004 NP predicts HF and CV Risk

4. STOP-HF Hypothesis  NP-driven screening and targeted collaborative care in the general at-risk population will decrease the prevalence of LVD and HF  39 collaborating primary care practices, intervention provided in a single referral center

5. STOP-HF Inclusion / Exclusion Entry Criteria – >40 years – Hypertension – Hyperlipidemia – Diabetes – Vascular disease – Arrhythmia – Obesity Primary End Point – Prevalence of heart failure (hospitalized) and asymptomatic left ventricular dysfunction Systolic Dysfunction: LVEF < 50% Diastolic Dysfunction: E / e prime > 15 Secondary End Point – Hospitalization for Cardiovascular Events (Time to event and Event rate) Heart Failure, Arrhythmia, Myocardial Infarction, Unstable angina, CVA, TIA, Peripheral Thrombosis, PE Excluded – Known LVSD or HF – Life-threatening illness – Refusal / inability to give informed consent

6. Study Flow n=3,123 n=1,374 n=677 n=697 Lost to follow up n=69 Withdrew consent n= 132 Lost to follow up n=69 Withdrew consent n= 132 Lost to follow up n=70 Withdrew consent n= 92 Lost to follow up n=70 Withdrew consent n= 92 Intention to treat analysis

7. Routine PCP care Annual BNP not available to clinicians At least annual review by PCP Cardiology review only if requested by PCP NP-directed care In addition to routine PCP care Annual BNP in all If BNP >50pg/ml at any time Shared-care – Cardiology review – Echo-Doppler – Other CV investigations – CV nurse coaching – Regular Cardiology follow-up STOP-HF Intervention

8. Demographics

10. Primary Endpoint – HF and LVD OR 0.59 [0.38, 0.90], p=0.01 OR 0.46 [0.27, 0.77], p=0.003 Total Population Any BNP > 50 pg/ml N=59 N=39 N=44 N=25

11. Endpoint – Time to First MACE OR 0.67 [0.46,0.98] p=0.04 OR 0.70 [0.47,1.03] p=0.07 Total Population Any BNP > 50 pg/ml Intervention Control

12. N=71 (10.5%)N=51 (7.3%) Event Rate OR 0.54 p=0.001 vs. Control Endpoint – MACE Event Rate

13. Therapies and Risk Factors 42 4352 5325 27 Baseline (%) SBP (mmHg) -9.2 -9.9 HR (bpm) 0.0 -1.2 LDL-C (mg/dL) 0.0 -2.9 BP significantly reduced within both groups (p<0.001) from baseline Increased use of RAAS modifying therapies in intervention group Trend to lower HR (p=0.09) and LDL-C (p=0.06) in high BNP subsets P= 0.02

14. Multifactorial Intervention Possible Mechanisms of benefit of NP based screening and collaborative care – Increased use of RAAS modifying therapies – Targeted CV investigations – Improved adherence, because of patient awareness of sequential BNP which may influence self-care – GP awareness of sequential BNP and influence on care in “high normals”

15. Limitations Self-selected primary care practices Non-blinding, regression to equivalence Multifactorial intervention – unlikely to be a single component which explains benefit Only included documented hospitalization events in MACE

16. Future Work Cost-effectiveness Other NP and clinical/demographic combinations Alternative multi-marker approachs “Specific therapies” for this at-risk cohort?

17. STOP-HF Conclusion Natriuretic peptide-based screening and collaborative care targeted 4 in 10 at-risk patients Reduced the rates of left ventricular dysfunction, heart failure, and emergency hospitalizations for major cardiovascular events.

18. STOP-HF Investigators Principal Investigators: Kenneth McDonald, MD Mark Ledwidge, PhD Co-investigators: Joseph Gallagher, MB Carmel Conlon, PhD Elaine Tallon, PGDip Eoin O Connell, MSc Ian Dawkins, PhD Chris Watson, PhD Rory O Hanlon, MD Margaret Bermingham,BPharm Anil Patle, MBA Gillian Murtagh, MD Victor Voon, MB Laura McDonald Brian Maurer, MD Funding Sources Heartbeat Trust Registered Charity CHY 15398 European Commission Framework Programme 7 Grant 261409 MEDIA Department of Health of Irish Government Health Services Executive St Vincent’s University Healthcare Group